Cardiology News

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

More than 140 million Americans use artificial sweeteners, a habit driven by the irrefutable fact that excess sugar is harmful. But I’m continually amazed by alarmist headlines on the topic.

In May, the World Health Organization (WHO) released a report to support its “conditional recommendation” against the use of non-sugar sweeteners (NSS) for weight control. Despite the WHO’s goal “to provide evidence-informed guidance,” the report includes the disclaimer that “The recommendation is based on evidence of low certainty.”

Low certainty is an accurate descriptor for the findings of many of the 280-plus studies in the report. That the guidance does not apply to patients with diabetes was easily lost in the repeated mentions of the perceived dangers of these sugar alternatives.

The review included various table-top and beverage sweeteners, including acesulfame K, aspartame, saccharin, sucralose, stevia, and stevia derivatives. Low-calorie sugars and sugar alcohols such as erythritol were excluded.

The WHO looked at long- and short-term trials, randomized controlled trials (RCTs), prospective studies, and case-control studies measuring a wide range of endpoints, from dental caries to cancer. The report highlighted that some findings cannot be attributed directly to NSS use but may simply be due to their substitution for sugar. Differences in outcomes due to sex, ethnicity, and body weight status could not be assessed either. And the WHO conceded the possibility of reverse causation in observational studies wherein higher-risk individuals may consume more NSS.

Nonnutritive sweeteners are given little credit for weight loss. “A significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake ... rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake),” the report reads. But isn’t the desired effect of using an artificial sweetener instead of table sugar that you lower your calorie intake?

The WHO noted that weight loss was not sustained – a finding in nearly every weight loss trial in history and something more attributable to human nature than the sweetener one chooses.

The document outlines that meta-analyses of prospective cohort studies show that higher intakes of NSS were associated with an increased risk for type 2 diabetes and elevated fasting glucose, while meta-analyses of randomized trials suggest no significant effect on “biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and hemoglobin A1c.”

Similar disparities are noted with cardiovascular risk. Prospective trials suggest an increased risk for CVD, including stroke and its precursor, hypertension; but again, the RCT data found no evidence to suggest a significant effect “on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein cholesterol and other blood lipids.”
 

Splenda and stevia under fire

Predictably, some in the nonnutritive sweetener industry are incensed.

Ted Gelov, CEO of Heartland Food Products Group, maker of Splenda, responded in a press release, “Every few years now it seems I have to come to you and clarify misleading headlines ... Suggesting that sweeteners like Splenda cannot have long-term benefits is a disservice to healthcare providers, their patients, and all consumers.”

Splenda has been on the U.S. market since 1999, and Mr. Gelov reportedly uses three to eight packets daily in his coffee and tea.

I reached out to Heartland and they sent me an eight-page document consisting of over 50 statements, summaries, and clinical trials supporting the safety of artificial sweeteners, including sucralose, an ingredient in Splenda. In 2016, Mr. Gelov rebutted claims that sucralose was linked to cancer in Swiss male mice. These “dramatized headlines are based on one flawed study by an isolated Italian research laboratory, the Ramazzini Institute,” Mr. Gelov wrote.

Another recent headline was about the DNA-damaging effects of sucralose-6-acetate (S6A) seen in an in vitro study published in the Journal of Toxicology and Environmental Health. According to the authors, commercial sucralose samples contain up to 0.67% S6A, a manufacturing impurity.

Despite many reports linking this study to Splenda, Heartland wrote that “Splenda and its ingredients were never studied or tested in this research. We, and our suppliers, rigorously and routinely test and monitor for any impurities in our products. We can confirm that S6A is not present in Splenda Brand sucralose down to the lowest detection limit possible, which is .001% sensitivity level.”

F. Perry Wilson, MD, director of Clinical and Translational Research Accelerator at Yale and a regular contributor to this news organization, took to Twitter to put this study in context: “The human exposure equivalent to sucralose would be 60 packets per day,” he pointed out. And the blood levels of S6A with normal consumption would not “come close to the DNA damage threshold noted in the article.”

Perhaps the most concerning scientific data suggesting a link between artificial sweetener use and ill health is a Cleveland Clinic study showing an association between higher blood levels of erythritol and adverse cardiovascular outcomes such as heart attack, stroke, or death. The researchers also found that erythritol, which is found in stevia and some keto food products, made platelet activation and clot formation easier.

When I asked about these findings, Heartland stated, “The study was primarily conducted on patients who were at an elevated risk of cardiovascular events due to their advanced age, elevated body mass and presence of pre-existing health conditions ... the stated findings were only an association and cannot imply causation.”

The main conclusion I’ve drawn on the topic of artificial sweeteners is that a lot of resources were wasted in performing underpowered, poorly designed trials on compounds that are already generally regarded as safe (GRAS) by the FDA. The WHO “conditional guideline” is, by its own description, based on a plethora of “low certainty” to “very low certainty” evidence.

The monies to produce the WHO report and many of these trials would have been better spent educating the public on the difference between simple and complex carbohydrates; the inflammatory and disease-producing effects of excess sugars; and how to prevent, diagnose, and treat diabetes.

If more trials on artificial sweeteners are planned, they should be performed on people doing human things – which does not include ingesting 60 packets of any sweetener in a single day.

In my personal N-of-1 trial, consuming sugar makes me crave more, feel sluggish, and gain weight. I don’t believe that NSS alone will control my weight. But I’ll continue to drink two cups of stevia-laced coffee every morning, take walks, avoid alcohol, eat my vegetables, and hope for the best.

Dr. Walton-Shirley is a clinical cardiologist in Nashville, Tenn. She disclosed no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

A version of this article first appeared on Medscape.com.

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

A version of this article first appeared on Medscape.com.

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

A version of this article first appeared on Medscape.com.

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

A version of this article first appeared on Medscape.com.

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

A version of this article first appeared on Medscape.com.

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



A version of this article first appeared on Medscape.com.

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



A version of this article first appeared on Medscape.com.

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



A version of this article first appeared on Medscape.com.

The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?

“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.

Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”

Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.

“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.

“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”

Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.

“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
 

Is CRP measurement necessary?

Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.

“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.

“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”

Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.

“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
 

‘An entire other axis driving atherosclerosis’

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.

“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.

“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”

Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”

Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”

Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”

He said that measurement of hsCRP is an appropriate way to select these patients.

“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
 

A second pillar of ASCVD treatment?

A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.

He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.

Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.

“So, the next step after a statin has to be to consider inflammation reduction,” he said.

“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.

“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.

“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.

Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.

If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”

Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.

“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
 

Polypharmacy concerns

Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.

“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.

“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.

“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.

“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
 

Safety is reassuring

In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.

“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”

Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”

Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
 

Part of the backbone of CV treatment?

Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.

“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.

“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”

Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.

A version of this article first appeared on Medscape.com.

The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?

“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.

Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”

Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.

“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.

“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”

Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.

“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
 

Is CRP measurement necessary?

Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.

“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.

“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”

Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.

“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
 

‘An entire other axis driving atherosclerosis’

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.

“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.

“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”

Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”

Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”

Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”

He said that measurement of hsCRP is an appropriate way to select these patients.

“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
 

A second pillar of ASCVD treatment?

A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.

He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.

Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.

“So, the next step after a statin has to be to consider inflammation reduction,” he said.

“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.

“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.

“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.

Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.

If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”

Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.

“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
 

Polypharmacy concerns

Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.

“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.

“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.

“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.

“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
 

Safety is reassuring

In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.

“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”

Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”

Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
 

Part of the backbone of CV treatment?

Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.

“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.

“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”

Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.

A version of this article first appeared on Medscape.com.

The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?

“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.

Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”

Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.

“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.

“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”

Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.

“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
 

Is CRP measurement necessary?

Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.

“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.

“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”

Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.

“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
 

‘An entire other axis driving atherosclerosis’

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.

“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.

“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”

Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”

Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”

Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”

He said that measurement of hsCRP is an appropriate way to select these patients.

“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
 

A second pillar of ASCVD treatment?

A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.

He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.

Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.

“So, the next step after a statin has to be to consider inflammation reduction,” he said.

“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.

“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.

“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.

Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.

If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”

Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.

“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
 

Polypharmacy concerns

Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.

“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.

“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.

“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.

“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
 

Safety is reassuring

In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.

“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”

Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”

Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
 

Part of the backbone of CV treatment?

Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.

“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.

“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”

Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.

A version of this article first appeared on Medscape.com.

TOPLINE:

There may be no threshold dose below which radiation to cardiac substructures does not increase the risk for later cardiac diseases in children with cancer.

METHODOLOGY:

• Review of 25,481 patients in the Childhood Cancer Survivor Study who had no cardiac complications in the first 5 years following cancer treatment from 1970 to 1999; nearly half (48.2%) had been exposed to radiotherapy.
• Radiation doses to the coronary arteries, heart chambers, heart valves, and whole heart were calculated based on radiotherapy records.
• Median age at follow up was 29.8 years and ranged from 5.6 to 65.9 years.

TAKEAWAY:

• Mean radiation doses of 5.0-9.9 Gy to the whole heart did not increase the risk for later cardiac disease.
• Mean doses of 5.0-9.9 Gy to the right coronary artery (rate ratio, 2.6) and left ventricle (RR, 2.2) did increase the risk for subsequent coronary artery disease.
• Mean doses of 5.0-9.9 Gy to the tricuspid valve (RR, 5.5) and right ventricle (RR, 8.4) increased the risk for later valvular disease.
• Linear modeling adequately described the dose-response relationship for many cardiac substructures, suggesting there is no threshold dose necessary for cardiac damage.

IN PRACTICE:

“These findings solidify the need to consider cardiac substructure doses in [pediatric] radiation treatment planning and in survivorship care. Future work to ascertain optimal cardiac dose constraints, especially in the era of highly conformal [radiotherapy] techniques such as [intensity-modulated radiotherapy] and proton therapy, remains critical,” the authors concluded.

STUDY DETAILS:

The study was led by James Bates, MD, of Emory University, Atlanta, and published in the Journal of Clinical Oncology.

LIMITATIONS:

Chronic conditions were self-reported.

Current radiotherapy techniques are much more precise than in the decades when these cancer survivors were treated, allowing preferential sparing of various heart structures.

The study did not assess other treatments and lifestyle issues that may have affected heart health.
 

DISCLOSURES:

The work was funded by the National Cancer Institute. Investigators reported ties to Doximity, Abbott, Merck, Grail, and other companies.

A version of this article first appeared on Medscape.com.

TOPLINE:

There may be no threshold dose below which radiation to cardiac substructures does not increase the risk for later cardiac diseases in children with cancer.

METHODOLOGY:

• Review of 25,481 patients in the Childhood Cancer Survivor Study who had no cardiac complications in the first 5 years following cancer treatment from 1970 to 1999; nearly half (48.2%) had been exposed to radiotherapy.
• Radiation doses to the coronary arteries, heart chambers, heart valves, and whole heart were calculated based on radiotherapy records.
• Median age at follow up was 29.8 years and ranged from 5.6 to 65.9 years.

TAKEAWAY:

• Mean radiation doses of 5.0-9.9 Gy to the whole heart did not increase the risk for later cardiac disease.
• Mean doses of 5.0-9.9 Gy to the right coronary artery (rate ratio, 2.6) and left ventricle (RR, 2.2) did increase the risk for subsequent coronary artery disease.
• Mean doses of 5.0-9.9 Gy to the tricuspid valve (RR, 5.5) and right ventricle (RR, 8.4) increased the risk for later valvular disease.
• Linear modeling adequately described the dose-response relationship for many cardiac substructures, suggesting there is no threshold dose necessary for cardiac damage.

IN PRACTICE:

“These findings solidify the need to consider cardiac substructure doses in [pediatric] radiation treatment planning and in survivorship care. Future work to ascertain optimal cardiac dose constraints, especially in the era of highly conformal [radiotherapy] techniques such as [intensity-modulated radiotherapy] and proton therapy, remains critical,” the authors concluded.

STUDY DETAILS:

The study was led by James Bates, MD, of Emory University, Atlanta, and published in the Journal of Clinical Oncology.

LIMITATIONS:

Chronic conditions were self-reported.

Current radiotherapy techniques are much more precise than in the decades when these cancer survivors were treated, allowing preferential sparing of various heart structures.

The study did not assess other treatments and lifestyle issues that may have affected heart health.
 

DISCLOSURES:

The work was funded by the National Cancer Institute. Investigators reported ties to Doximity, Abbott, Merck, Grail, and other companies.

A version of this article first appeared on Medscape.com.

TOPLINE:

There may be no threshold dose below which radiation to cardiac substructures does not increase the risk for later cardiac diseases in children with cancer.

METHODOLOGY:

• Review of 25,481 patients in the Childhood Cancer Survivor Study who had no cardiac complications in the first 5 years following cancer treatment from 1970 to 1999; nearly half (48.2%) had been exposed to radiotherapy.
• Radiation doses to the coronary arteries, heart chambers, heart valves, and whole heart were calculated based on radiotherapy records.
• Median age at follow up was 29.8 years and ranged from 5.6 to 65.9 years.

TAKEAWAY:

• Mean radiation doses of 5.0-9.9 Gy to the whole heart did not increase the risk for later cardiac disease.
• Mean doses of 5.0-9.9 Gy to the right coronary artery (rate ratio, 2.6) and left ventricle (RR, 2.2) did increase the risk for subsequent coronary artery disease.
• Mean doses of 5.0-9.9 Gy to the tricuspid valve (RR, 5.5) and right ventricle (RR, 8.4) increased the risk for later valvular disease.
• Linear modeling adequately described the dose-response relationship for many cardiac substructures, suggesting there is no threshold dose necessary for cardiac damage.

IN PRACTICE:

“These findings solidify the need to consider cardiac substructure doses in [pediatric] radiation treatment planning and in survivorship care. Future work to ascertain optimal cardiac dose constraints, especially in the era of highly conformal [radiotherapy] techniques such as [intensity-modulated radiotherapy] and proton therapy, remains critical,” the authors concluded.

STUDY DETAILS:

The study was led by James Bates, MD, of Emory University, Atlanta, and published in the Journal of Clinical Oncology.

LIMITATIONS:

Chronic conditions were self-reported.

Current radiotherapy techniques are much more precise than in the decades when these cancer survivors were treated, allowing preferential sparing of various heart structures.

The study did not assess other treatments and lifestyle issues that may have affected heart health.
 

DISCLOSURES:

The work was funded by the National Cancer Institute. Investigators reported ties to Doximity, Abbott, Merck, Grail, and other companies.

A version of this article first appeared on Medscape.com.

Most patients aren’t receiving all the medications they should based on guidelines, nor are they getting them at the most effective time in their disease course, suggests a registry study of patients in the United States hospitalized with heart failure with reduced ejection fraction (HFrEF).

Only a sixth were on all guideline-directed medical therapies (GDMTs) at admission, but that improved to one-third by discharge. On average, one such medication was initiated per patient for every 6 days in the hospital.

Shortfalls in predischarge GDMT initiation disproportionately landed on women, patients at rural centers, and those with renal failure or other comorbidities. But they didn’t seem related to patient race or ethnicity in the study reported in JACC: Heart Failure.

The analysis covers the 3 years preceding the May 2020 first-time approval of a sodium-glucose cotransporter 2 (SGLT2) inhibitor for nondiabetic patients with HFrEF, and therefore doesn’t cover such drugs for that indication. The SGLT2 inhibitors would later join beta-blockers, renin-angiotensin system (RAS) inhibitors, and mineralocorticoid receptor antagonists (MRAs) in the quartet of core GDMT medications broadly indicated for HFrEF.

In-hospital initiation of GDMT for HFrEF is considered a predictor of being on those medications after discharge and is itself guideline recommended. There’s clear evidence that treatment with the four core medications boosts survival and cuts rehospitalization risk, and that “getting those on board as soon as possible will eventually benefit many patients,” Paul L. Hess, MD, MHS, said in an interview.

Dr. Hess, University of Colorado Anschutz Medical Campus, Aurora, is senior author on the report from the Get With The Guidelines–Heart Failure (GWTG-HF) quality improvement program of the American Heart Association.

Broad uptake of new medical therapies into practice may sometimes take 15 or more years from first publication, Dr. Hess said, so, “I find it encouraging in the study that over a shorter time period, 2017-2020, there was improvement.”

Indeed, the odds of in-hospital initiation of an indicated med during that period on average climbed a significant 8% every 3 months, the report states.

The finding suggests that “heart failure hospitalization is, in and of itself, an important intervention for getting folks on the appropriate medications,” Dr. Hess said. It also means “we’re getting better at it,” at least at the study’s 160 GWTG-HF participating hospitals nationwide.

Those centers, the report acknowledges, varied in size, geography, and teaching status but were not necessarily representative of all U.S. hospitals. In another potential limitation, the study couldn’t account for patients who weren’t prescribed all indicated medications for clinically valid reasons. It excluded patients with “clear contraindications,” Dr. Hess said. But there could have been “legitimate reasons” some indicated medications weren’t always prescribed, including patient frailty, hemodynamic intolerance, renal dysfunction, or polypharmacy concerns.

“Positive takeaways” from the analysis, notes an accompanying editorial, include improved prescription rates for key GDMT categories across more than 3 years of data, and evidence that in-hospital initiation “was feasible and, at least for some medications, reliably undertaken.”

Of note, new GDMT prescriptions from admission to discharge went from 70% to almost 98% for beta-blockers, from 59% to about 91% for RAS inhibitors, from about 26% to 56% for MRAs, and from 15.5% to 27.4% for hydralazine/nitrates, wrote Karen E. Joynt Maddox, MD, MPH, and Daniel K. Fox, MD, PhD, both of Washington University in St. Louis.

“Key areas for improvement,” they noted, include prescriptions for women, who were 12% less likely than men to have appropriate GDMT initiated during hospitalization (P < .001); and practice at rural hospitals, which were 40% less likely than urban centers to have patients on full GDMT by discharge (P = .017).

Although only 2.6% of the GWTG-HF centers were in rural locations, “rural hospitals make up approximately one-third of general acute care hospitals in this country,” the editorial states. They therefore “represent a key source of health disparity” in the United States in need of further study.

The analysis of 50,170 patients hospitalized with HFrEF compared the number of GDMT medications for which they were eligible, on at-hospital admission, and by discharge.

The drug categories included “evidence based beta blockers,” that is, bisoprolol, carvedilol, or sustained-release metoprolol; RAS inhibitors, specifically ACE inhibitors, angiotensin receptor blockers, or sacubitril/valsartan (Entresto); MRAs; SGLT2 inhibitors in patients with diabetes; diuretics for congestion; oral anticoagulants for atrial fibrillation; and hydralazine/nitrates in African Americans.

About 15% of the patients at hospital admission were on all indicated HFrEF medications for which they were eligible. The proportion more than doubled to 32.8% by discharge.

Factors significantly associated with reduced odds for in-hospital GDMT initiation include older age (odds ratio, 0.94 per 5-year increment), being female versus male (OR, 0.88), rural location (OR, 0.60), Medicaid versus Medicare or private insurance (OR, 0.93), stroke history (OR, 0.91), peripheral artery disease (OR, 0.93), chronic obstructive pulmonary disease or asthma (OR, 0.86), and renal insufficiency (OR, 0.77).

The findings suggest that there has been at least some progress in getting hospitalized patients “on the right meds” by discharge, Dr. Hess observed. To help address shortfalls in some patient groups, “there is interest in engaging pharmacists in helping us encourage providers on the front lines to initiate and titrate medications.”

The GWTG-HF program is sponsored, in part, by Novartis, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Bayer, Tylenol, and Alnylam Pharmaceuticals. Dr. Hess disclosed no relevant financial relationships. Dr. Maddox disclosed serving on the Health Policy Advisory Council for Centene. Dr. Fox reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Most patients aren’t receiving all the medications they should based on guidelines, nor are they getting them at the most effective time in their disease course, suggests a registry study of patients in the United States hospitalized with heart failure with reduced ejection fraction (HFrEF).

Only a sixth were on all guideline-directed medical therapies (GDMTs) at admission, but that improved to one-third by discharge. On average, one such medication was initiated per patient for every 6 days in the hospital.

Shortfalls in predischarge GDMT initiation disproportionately landed on women, patients at rural centers, and those with renal failure or other comorbidities. But they didn’t seem related to patient race or ethnicity in the study reported in JACC: Heart Failure.

The analysis covers the 3 years preceding the May 2020 first-time approval of a sodium-glucose cotransporter 2 (SGLT2) inhibitor for nondiabetic patients with HFrEF, and therefore doesn’t cover such drugs for that indication. The SGLT2 inhibitors would later join beta-blockers, renin-angiotensin system (RAS) inhibitors, and mineralocorticoid receptor antagonists (MRAs) in the quartet of core GDMT medications broadly indicated for HFrEF.

In-hospital initiation of GDMT for HFrEF is considered a predictor of being on those medications after discharge and is itself guideline recommended. There’s clear evidence that treatment with the four core medications boosts survival and cuts rehospitalization risk, and that “getting those on board as soon as possible will eventually benefit many patients,” Paul L. Hess, MD, MHS, said in an interview.

Dr. Hess, University of Colorado Anschutz Medical Campus, Aurora, is senior author on the report from the Get With The Guidelines–Heart Failure (GWTG-HF) quality improvement program of the American Heart Association.

Broad uptake of new medical therapies into practice may sometimes take 15 or more years from first publication, Dr. Hess said, so, “I find it encouraging in the study that over a shorter time period, 2017-2020, there was improvement.”

Indeed, the odds of in-hospital initiation of an indicated med during that period on average climbed a significant 8% every 3 months, the report states.

The finding suggests that “heart failure hospitalization is, in and of itself, an important intervention for getting folks on the appropriate medications,” Dr. Hess said. It also means “we’re getting better at it,” at least at the study’s 160 GWTG-HF participating hospitals nationwide.

Those centers, the report acknowledges, varied in size, geography, and teaching status but were not necessarily representative of all U.S. hospitals. In another potential limitation, the study couldn’t account for patients who weren’t prescribed all indicated medications for clinically valid reasons. It excluded patients with “clear contraindications,” Dr. Hess said. But there could have been “legitimate reasons” some indicated medications weren’t always prescribed, including patient frailty, hemodynamic intolerance, renal dysfunction, or polypharmacy concerns.

“Positive takeaways” from the analysis, notes an accompanying editorial, include improved prescription rates for key GDMT categories across more than 3 years of data, and evidence that in-hospital initiation “was feasible and, at least for some medications, reliably undertaken.”

Of note, new GDMT prescriptions from admission to discharge went from 70% to almost 98% for beta-blockers, from 59% to about 91% for RAS inhibitors, from about 26% to 56% for MRAs, and from 15.5% to 27.4% for hydralazine/nitrates, wrote Karen E. Joynt Maddox, MD, MPH, and Daniel K. Fox, MD, PhD, both of Washington University in St. Louis.

“Key areas for improvement,” they noted, include prescriptions for women, who were 12% less likely than men to have appropriate GDMT initiated during hospitalization (P < .001); and practice at rural hospitals, which were 40% less likely than urban centers to have patients on full GDMT by discharge (P = .017).

Although only 2.6% of the GWTG-HF centers were in rural locations, “rural hospitals make up approximately one-third of general acute care hospitals in this country,” the editorial states. They therefore “represent a key source of health disparity” in the United States in need of further study.

The analysis of 50,170 patients hospitalized with HFrEF compared the number of GDMT medications for which they were eligible, on at-hospital admission, and by discharge.

The drug categories included “evidence based beta blockers,” that is, bisoprolol, carvedilol, or sustained-release metoprolol; RAS inhibitors, specifically ACE inhibitors, angiotensin receptor blockers, or sacubitril/valsartan (Entresto); MRAs; SGLT2 inhibitors in patients with diabetes; diuretics for congestion; oral anticoagulants for atrial fibrillation; and hydralazine/nitrates in African Americans.

About 15% of the patients at hospital admission were on all indicated HFrEF medications for which they were eligible. The proportion more than doubled to 32.8% by discharge.

Factors significantly associated with reduced odds for in-hospital GDMT initiation include older age (odds ratio, 0.94 per 5-year increment), being female versus male (OR, 0.88), rural location (OR, 0.60), Medicaid versus Medicare or private insurance (OR, 0.93), stroke history (OR, 0.91), peripheral artery disease (OR, 0.93), chronic obstructive pulmonary disease or asthma (OR, 0.86), and renal insufficiency (OR, 0.77).

The findings suggest that there has been at least some progress in getting hospitalized patients “on the right meds” by discharge, Dr. Hess observed. To help address shortfalls in some patient groups, “there is interest in engaging pharmacists in helping us encourage providers on the front lines to initiate and titrate medications.”

The GWTG-HF program is sponsored, in part, by Novartis, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Bayer, Tylenol, and Alnylam Pharmaceuticals. Dr. Hess disclosed no relevant financial relationships. Dr. Maddox disclosed serving on the Health Policy Advisory Council for Centene. Dr. Fox reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Most patients aren’t receiving all the medications they should based on guidelines, nor are they getting them at the most effective time in their disease course, suggests a registry study of patients in the United States hospitalized with heart failure with reduced ejection fraction (HFrEF).

Only a sixth were on all guideline-directed medical therapies (GDMTs) at admission, but that improved to one-third by discharge. On average, one such medication was initiated per patient for every 6 days in the hospital.

Shortfalls in predischarge GDMT initiation disproportionately landed on women, patients at rural centers, and those with renal failure or other comorbidities. But they didn’t seem related to patient race or ethnicity in the study reported in JACC: Heart Failure.

The analysis covers the 3 years preceding the May 2020 first-time approval of a sodium-glucose cotransporter 2 (SGLT2) inhibitor for nondiabetic patients with HFrEF, and therefore doesn’t cover such drugs for that indication. The SGLT2 inhibitors would later join beta-blockers, renin-angiotensin system (RAS) inhibitors, and mineralocorticoid receptor antagonists (MRAs) in the quartet of core GDMT medications broadly indicated for HFrEF.

In-hospital initiation of GDMT for HFrEF is considered a predictor of being on those medications after discharge and is itself guideline recommended. There’s clear evidence that treatment with the four core medications boosts survival and cuts rehospitalization risk, and that “getting those on board as soon as possible will eventually benefit many patients,” Paul L. Hess, MD, MHS, said in an interview.

Dr. Hess, University of Colorado Anschutz Medical Campus, Aurora, is senior author on the report from the Get With The Guidelines–Heart Failure (GWTG-HF) quality improvement program of the American Heart Association.

Broad uptake of new medical therapies into practice may sometimes take 15 or more years from first publication, Dr. Hess said, so, “I find it encouraging in the study that over a shorter time period, 2017-2020, there was improvement.”

Indeed, the odds of in-hospital initiation of an indicated med during that period on average climbed a significant 8% every 3 months, the report states.

The finding suggests that “heart failure hospitalization is, in and of itself, an important intervention for getting folks on the appropriate medications,” Dr. Hess said. It also means “we’re getting better at it,” at least at the study’s 160 GWTG-HF participating hospitals nationwide.

Those centers, the report acknowledges, varied in size, geography, and teaching status but were not necessarily representative of all U.S. hospitals. In another potential limitation, the study couldn’t account for patients who weren’t prescribed all indicated medications for clinically valid reasons. It excluded patients with “clear contraindications,” Dr. Hess said. But there could have been “legitimate reasons” some indicated medications weren’t always prescribed, including patient frailty, hemodynamic intolerance, renal dysfunction, or polypharmacy concerns.

“Positive takeaways” from the analysis, notes an accompanying editorial, include improved prescription rates for key GDMT categories across more than 3 years of data, and evidence that in-hospital initiation “was feasible and, at least for some medications, reliably undertaken.”

Of note, new GDMT prescriptions from admission to discharge went from 70% to almost 98% for beta-blockers, from 59% to about 91% for RAS inhibitors, from about 26% to 56% for MRAs, and from 15.5% to 27.4% for hydralazine/nitrates, wrote Karen E. Joynt Maddox, MD, MPH, and Daniel K. Fox, MD, PhD, both of Washington University in St. Louis.

“Key areas for improvement,” they noted, include prescriptions for women, who were 12% less likely than men to have appropriate GDMT initiated during hospitalization (P < .001); and practice at rural hospitals, which were 40% less likely than urban centers to have patients on full GDMT by discharge (P = .017).

Although only 2.6% of the GWTG-HF centers were in rural locations, “rural hospitals make up approximately one-third of general acute care hospitals in this country,” the editorial states. They therefore “represent a key source of health disparity” in the United States in need of further study.

The analysis of 50,170 patients hospitalized with HFrEF compared the number of GDMT medications for which they were eligible, on at-hospital admission, and by discharge.

The drug categories included “evidence based beta blockers,” that is, bisoprolol, carvedilol, or sustained-release metoprolol; RAS inhibitors, specifically ACE inhibitors, angiotensin receptor blockers, or sacubitril/valsartan (Entresto); MRAs; SGLT2 inhibitors in patients with diabetes; diuretics for congestion; oral anticoagulants for atrial fibrillation; and hydralazine/nitrates in African Americans.

About 15% of the patients at hospital admission were on all indicated HFrEF medications for which they were eligible. The proportion more than doubled to 32.8% by discharge.

Factors significantly associated with reduced odds for in-hospital GDMT initiation include older age (odds ratio, 0.94 per 5-year increment), being female versus male (OR, 0.88), rural location (OR, 0.60), Medicaid versus Medicare or private insurance (OR, 0.93), stroke history (OR, 0.91), peripheral artery disease (OR, 0.93), chronic obstructive pulmonary disease or asthma (OR, 0.86), and renal insufficiency (OR, 0.77).

The findings suggest that there has been at least some progress in getting hospitalized patients “on the right meds” by discharge, Dr. Hess observed. To help address shortfalls in some patient groups, “there is interest in engaging pharmacists in helping us encourage providers on the front lines to initiate and titrate medications.”

The GWTG-HF program is sponsored, in part, by Novartis, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Bayer, Tylenol, and Alnylam Pharmaceuticals. Dr. Hess disclosed no relevant financial relationships. Dr. Maddox disclosed serving on the Health Policy Advisory Council for Centene. Dr. Fox reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Some patients continually cancel their appointments, ignore your medical directions, treat your staff rudely, or send you harassing emails.

Do you have to tolerate their behavior?

No, these are all appropriate reasons to terminate patients, attorneys say. Patients also can be dismissed for misleading doctors about their past medical history, chronic drug-seeking, displaying threatening or seductive behavior toward staff members or physicians, or any criminal behavior in the office, experts say.

But even if a reason seems legitimate, that doesn’t make it legal. Doctors should consider whether the reason is legal, said Chicago-area attorney Ericka Adler, JD, a partner at Roetzel & Andress, who advises doctors about terminating patients.

“Although a physician may think a reason to terminate a patient is legitimate, they should always be mindful of whether there is a legal concern at issue and consult with counsel if they’re unsure,” Ms. Adler said.

Terminating patients for an “illegal” reason such as discrimination based on race or gender or sexual orientation – even if couched as a legitimate patient issue – could open the practice to a lawsuit, Ms. Adler said.

Doctors also want to avoid patient abandonment claims by talking to the patient about problems and documenting them as they arise. If they can’t be resolved, doctors should ensure that there’s continuity of care when patients change physicians, said Ms. Adler.

About 90% of physicians have dismissed at least one patient during their career, according to a study of nearly 800 primary care practices. The most common reasons were legitimate: a patient was “extremely disruptive and/or behaved inappropriately toward clinicians or staff”; a patient had “violated chronic pain and controlled substance policies”; and a patient had “repeatedly missed appointments.” 

Jacqui O’Kane, DO, a family physician at South Georgia Medical Center in rural Nashville, said she has dismissed about 15 of 3,000 patients she has seen in the past 3 years at the clinic. Before she dismisses a patient, she looks at whether there has been a pattern of behavior and tries to talk to them about the problem first to find out if there are other reasons for it.

She also gives patients a warning: If the unacceptable behavior continues, it will lead to their dismissal.
 

When patients cross a line

Dr. O’Kane warned an elderly man who used the N-word with her that she wouldn’t tolerate that language in her office. Then, when he later called her front office employee the N-word, she decided to dismiss him.

“I said, ‘That’s it, you can’t say that to someone in this office. I already told you once, and you did it again. I’m sorry, you have to find another doctor,’ ” said Dr. O’Kane.

Another patient crossed a line when she missed four appointments, refused to come in, and kept sending Dr. O’Kane long messages on MyChart demanding medications and advice. One message was fairly obtrusive: “If you don’t give me something stronger for my nerves TODAY, I am going to LOSE MY MIND!!!” Dr. O’Kane said the patient wrote.

“I then told her that’s not how I run my practice and that she needed to find someone else.”

Another common reason doctors dismiss patients is for nonpayment, says Ms. Adler.

Recently, however, some patients have also begun demanding their money back from doctors for services already received and billed because they were unhappy about something that occurred at the doctor’s office, said Ms. Adler.

“I advise doctors to respond: ‘We disagree that you didn’t get the service, but we will give you your money back, and we’re also terminating you from our practice.’  At that point, the doctor-patient relationship has become impossible,” said Ms. Adler.
 

How to dismiss difficult patients ethically and legally

According to the AMA’s Council on Ethical and Judicial Affairs, a physician may not discontinue treatment of a patient if further treatment is medically indicated without giving the patient reasonable notice and sufficient opportunity to make alternative arrangements for care.

Terminating a patient abruptly without transferring their care could lead to a claim of patient abandonment and the physician being called before a licensing board for potentially violating the state’s Medical Practice Act, said Ms. Adler.

Doctors can take these six steps to set the stage for dismissal and avoid a claim of patient abandonment.

1. Create written policies. Medical practices can describe the rules and behavior they expect from patients in these policies, which can cover, for example, payment, treating staff with courtesy, and medications. “When the rules are in writing and patients sign off on them, that gives doctors a certain comfort level in being able to refer to them and say that the patient hasn’t been compliant,” said Ms. Adler.

She also recommends that your practice create a policy that doctors should let the patient know about their concerns and meet with them to discuss the problem before receiving a termination letter.

2. Document any consistent problems you’re having with a patient. When you start having problems with a patient, you should document when the problem occurred, how often it occurred, any discussions with the patient about the problem, warnings you gave the patient, and if and when you decided to terminate the patient.

3. Meet with the patient to discuss the problem. “Talking and meeting with a patient also allows the physician to assess whether there’s another issue. For example, is there a mental health concern? Is there a financial reason for nonpayment or no-shows? There are multiple benefits to finding out what the problem is,” said Ms. Adler.

Once you’ve decided to terminate a patient, here’s what you should do:

4. Allow enough time for the patient to find alternative care. Ms. Adler recommends giving patients 30 days’ notice and that physicians offer to provide emergency care during that time. However, if the patient is undergoing treatment or has other challenges, more time may be needed to transfer care.

“It’s important to consider the patient’s context – if the patient is receiving cancer treatment, or is in a late stage of pregnancy, or lives in a rural area where few specialists are available, you may want to treat them longer – at least until they finish their treatment,” said Ms. Adler. Also, states may have their own requirements about minimum notice periods, she said.

5. Provide patients with written notice that you intend to terminate their care. Ms. Adler recommends that each letter be tailored to the patient’s specific circumstances. “You could spell out a patient’s history of noncompliance or nonpayment or inappropriate conduct because it’s been documented and the patient is already aware of it from a previous discussion,” she said.

Ms. Adler also recommends that doctors consult with legal counsel when in doubt or if contacted by the patient’s lawyer. Some lawyers will draft the termination letters, she said.

6. Include the following information in the written letter: The date that they will no longer receive care, how they can obtain copies of their medical records, and how they can find a new physician by providing contact information for a state medical association or similar organization, which often maintains a database of clinicians by specialty and location.

The letter should also state that the doctor will provide emergency care during the 30 days. Ms. Adler also recommends sending the notice by certified mail.

Dr. O’Kane said she may be more likely to give patients a second chance because she practices in a rural underserved area, and she understands that her patients don’t have many other options for health care. She also has developed a reputation for being willing to take on difficult patients that other physicians didn’t want to deal with, she said.

She encourages physicians to talk to patients to find out why, for example, they may not be compliant with medications.

“The patient may say, ‘I had to choose between paying for medications and putting food on the table,’ ” said Dr. O’Kane.

A version of this article first appeared on Medscape.com.

Some patients continually cancel their appointments, ignore your medical directions, treat your staff rudely, or send you harassing emails.

Do you have to tolerate their behavior?

No, these are all appropriate reasons to terminate patients, attorneys say. Patients also can be dismissed for misleading doctors about their past medical history, chronic drug-seeking, displaying threatening or seductive behavior toward staff members or physicians, or any criminal behavior in the office, experts say.

But even if a reason seems legitimate, that doesn’t make it legal. Doctors should consider whether the reason is legal, said Chicago-area attorney Ericka Adler, JD, a partner at Roetzel & Andress, who advises doctors about terminating patients.

“Although a physician may think a reason to terminate a patient is legitimate, they should always be mindful of whether there is a legal concern at issue and consult with counsel if they’re unsure,” Ms. Adler said.

Terminating patients for an “illegal” reason such as discrimination based on race or gender or sexual orientation – even if couched as a legitimate patient issue – could open the practice to a lawsuit, Ms. Adler said.

Doctors also want to avoid patient abandonment claims by talking to the patient about problems and documenting them as they arise. If they can’t be resolved, doctors should ensure that there’s continuity of care when patients change physicians, said Ms. Adler.

About 90% of physicians have dismissed at least one patient during their career, according to a study of nearly 800 primary care practices. The most common reasons were legitimate: a patient was “extremely disruptive and/or behaved inappropriately toward clinicians or staff”; a patient had “violated chronic pain and controlled substance policies”; and a patient had “repeatedly missed appointments.” 

Jacqui O’Kane, DO, a family physician at South Georgia Medical Center in rural Nashville, said she has dismissed about 15 of 3,000 patients she has seen in the past 3 years at the clinic. Before she dismisses a patient, she looks at whether there has been a pattern of behavior and tries to talk to them about the problem first to find out if there are other reasons for it.

She also gives patients a warning: If the unacceptable behavior continues, it will lead to their dismissal.
 

When patients cross a line

Dr. O’Kane warned an elderly man who used the N-word with her that she wouldn’t tolerate that language in her office. Then, when he later called her front office employee the N-word, she decided to dismiss him.

“I said, ‘That’s it, you can’t say that to someone in this office. I already told you once, and you did it again. I’m sorry, you have to find another doctor,’ ” said Dr. O’Kane.

Another patient crossed a line when she missed four appointments, refused to come in, and kept sending Dr. O’Kane long messages on MyChart demanding medications and advice. One message was fairly obtrusive: “If you don’t give me something stronger for my nerves TODAY, I am going to LOSE MY MIND!!!” Dr. O’Kane said the patient wrote.

“I then told her that’s not how I run my practice and that she needed to find someone else.”

Another common reason doctors dismiss patients is for nonpayment, says Ms. Adler.

Recently, however, some patients have also begun demanding their money back from doctors for services already received and billed because they were unhappy about something that occurred at the doctor’s office, said Ms. Adler.

“I advise doctors to respond: ‘We disagree that you didn’t get the service, but we will give you your money back, and we’re also terminating you from our practice.’  At that point, the doctor-patient relationship has become impossible,” said Ms. Adler.
 

How to dismiss difficult patients ethically and legally

According to the AMA’s Council on Ethical and Judicial Affairs, a physician may not discontinue treatment of a patient if further treatment is medically indicated without giving the patient reasonable notice and sufficient opportunity to make alternative arrangements for care.

Terminating a patient abruptly without transferring their care could lead to a claim of patient abandonment and the physician being called before a licensing board for potentially violating the state’s Medical Practice Act, said Ms. Adler.

Doctors can take these six steps to set the stage for dismissal and avoid a claim of patient abandonment.

1. Create written policies. Medical practices can describe the rules and behavior they expect from patients in these policies, which can cover, for example, payment, treating staff with courtesy, and medications. “When the rules are in writing and patients sign off on them, that gives doctors a certain comfort level in being able to refer to them and say that the patient hasn’t been compliant,” said Ms. Adler.

She also recommends that your practice create a policy that doctors should let the patient know about their concerns and meet with them to discuss the problem before receiving a termination letter.

2. Document any consistent problems you’re having with a patient. When you start having problems with a patient, you should document when the problem occurred, how often it occurred, any discussions with the patient about the problem, warnings you gave the patient, and if and when you decided to terminate the patient.

3. Meet with the patient to discuss the problem. “Talking and meeting with a patient also allows the physician to assess whether there’s another issue. For example, is there a mental health concern? Is there a financial reason for nonpayment or no-shows? There are multiple benefits to finding out what the problem is,” said Ms. Adler.

Once you’ve decided to terminate a patient, here’s what you should do:

4. Allow enough time for the patient to find alternative care. Ms. Adler recommends giving patients 30 days’ notice and that physicians offer to provide emergency care during that time. However, if the patient is undergoing treatment or has other challenges, more time may be needed to transfer care.

“It’s important to consider the patient’s context – if the patient is receiving cancer treatment, or is in a late stage of pregnancy, or lives in a rural area where few specialists are available, you may want to treat them longer – at least until they finish their treatment,” said Ms. Adler. Also, states may have their own requirements about minimum notice periods, she said.

5. Provide patients with written notice that you intend to terminate their care. Ms. Adler recommends that each letter be tailored to the patient’s specific circumstances. “You could spell out a patient’s history of noncompliance or nonpayment or inappropriate conduct because it’s been documented and the patient is already aware of it from a previous discussion,” she said.

Ms. Adler also recommends that doctors consult with legal counsel when in doubt or if contacted by the patient’s lawyer. Some lawyers will draft the termination letters, she said.

6. Include the following information in the written letter: The date that they will no longer receive care, how they can obtain copies of their medical records, and how they can find a new physician by providing contact information for a state medical association or similar organization, which often maintains a database of clinicians by specialty and location.

The letter should also state that the doctor will provide emergency care during the 30 days. Ms. Adler also recommends sending the notice by certified mail.

Dr. O’Kane said she may be more likely to give patients a second chance because she practices in a rural underserved area, and she understands that her patients don’t have many other options for health care. She also has developed a reputation for being willing to take on difficult patients that other physicians didn’t want to deal with, she said.

She encourages physicians to talk to patients to find out why, for example, they may not be compliant with medications.

“The patient may say, ‘I had to choose between paying for medications and putting food on the table,’ ” said Dr. O’Kane.

A version of this article first appeared on Medscape.com.

Some patients continually cancel their appointments, ignore your medical directions, treat your staff rudely, or send you harassing emails.

Do you have to tolerate their behavior?

No, these are all appropriate reasons to terminate patients, attorneys say. Patients also can be dismissed for misleading doctors about their past medical history, chronic drug-seeking, displaying threatening or seductive behavior toward staff members or physicians, or any criminal behavior in the office, experts say.

But even if a reason seems legitimate, that doesn’t make it legal. Doctors should consider whether the reason is legal, said Chicago-area attorney Ericka Adler, JD, a partner at Roetzel & Andress, who advises doctors about terminating patients.

“Although a physician may think a reason to terminate a patient is legitimate, they should always be mindful of whether there is a legal concern at issue and consult with counsel if they’re unsure,” Ms. Adler said.

Terminating patients for an “illegal” reason such as discrimination based on race or gender or sexual orientation – even if couched as a legitimate patient issue – could open the practice to a lawsuit, Ms. Adler said.

Doctors also want to avoid patient abandonment claims by talking to the patient about problems and documenting them as they arise. If they can’t be resolved, doctors should ensure that there’s continuity of care when patients change physicians, said Ms. Adler.

About 90% of physicians have dismissed at least one patient during their career, according to a study of nearly 800 primary care practices. The most common reasons were legitimate: a patient was “extremely disruptive and/or behaved inappropriately toward clinicians or staff”; a patient had “violated chronic pain and controlled substance policies”; and a patient had “repeatedly missed appointments.” 

Jacqui O’Kane, DO, a family physician at South Georgia Medical Center in rural Nashville, said she has dismissed about 15 of 3,000 patients she has seen in the past 3 years at the clinic. Before she dismisses a patient, she looks at whether there has been a pattern of behavior and tries to talk to them about the problem first to find out if there are other reasons for it.

She also gives patients a warning: If the unacceptable behavior continues, it will lead to their dismissal.
 

When patients cross a line

Dr. O’Kane warned an elderly man who used the N-word with her that she wouldn’t tolerate that language in her office. Then, when he later called her front office employee the N-word, she decided to dismiss him.

“I said, ‘That’s it, you can’t say that to someone in this office. I already told you once, and you did it again. I’m sorry, you have to find another doctor,’ ” said Dr. O’Kane.

Another patient crossed a line when she missed four appointments, refused to come in, and kept sending Dr. O’Kane long messages on MyChart demanding medications and advice. One message was fairly obtrusive: “If you don’t give me something stronger for my nerves TODAY, I am going to LOSE MY MIND!!!” Dr. O’Kane said the patient wrote.

“I then told her that’s not how I run my practice and that she needed to find someone else.”

Another common reason doctors dismiss patients is for nonpayment, says Ms. Adler.

Recently, however, some patients have also begun demanding their money back from doctors for services already received and billed because they were unhappy about something that occurred at the doctor’s office, said Ms. Adler.

“I advise doctors to respond: ‘We disagree that you didn’t get the service, but we will give you your money back, and we’re also terminating you from our practice.’  At that point, the doctor-patient relationship has become impossible,” said Ms. Adler.
 

How to dismiss difficult patients ethically and legally

According to the AMA’s Council on Ethical and Judicial Affairs, a physician may not discontinue treatment of a patient if further treatment is medically indicated without giving the patient reasonable notice and sufficient opportunity to make alternative arrangements for care.

Terminating a patient abruptly without transferring their care could lead to a claim of patient abandonment and the physician being called before a licensing board for potentially violating the state’s Medical Practice Act, said Ms. Adler.

Doctors can take these six steps to set the stage for dismissal and avoid a claim of patient abandonment.

1. Create written policies. Medical practices can describe the rules and behavior they expect from patients in these policies, which can cover, for example, payment, treating staff with courtesy, and medications. “When the rules are in writing and patients sign off on them, that gives doctors a certain comfort level in being able to refer to them and say that the patient hasn’t been compliant,” said Ms. Adler.

She also recommends that your practice create a policy that doctors should let the patient know about their concerns and meet with them to discuss the problem before receiving a termination letter.

2. Document any consistent problems you’re having with a patient. When you start having problems with a patient, you should document when the problem occurred, how often it occurred, any discussions with the patient about the problem, warnings you gave the patient, and if and when you decided to terminate the patient.

3. Meet with the patient to discuss the problem. “Talking and meeting with a patient also allows the physician to assess whether there’s another issue. For example, is there a mental health concern? Is there a financial reason for nonpayment or no-shows? There are multiple benefits to finding out what the problem is,” said Ms. Adler.

Once you’ve decided to terminate a patient, here’s what you should do:

4. Allow enough time for the patient to find alternative care. Ms. Adler recommends giving patients 30 days’ notice and that physicians offer to provide emergency care during that time. However, if the patient is undergoing treatment or has other challenges, more time may be needed to transfer care.

“It’s important to consider the patient’s context – if the patient is receiving cancer treatment, or is in a late stage of pregnancy, or lives in a rural area where few specialists are available, you may want to treat them longer – at least until they finish their treatment,” said Ms. Adler. Also, states may have their own requirements about minimum notice periods, she said.

5. Provide patients with written notice that you intend to terminate their care. Ms. Adler recommends that each letter be tailored to the patient’s specific circumstances. “You could spell out a patient’s history of noncompliance or nonpayment or inappropriate conduct because it’s been documented and the patient is already aware of it from a previous discussion,” she said.

Ms. Adler also recommends that doctors consult with legal counsel when in doubt or if contacted by the patient’s lawyer. Some lawyers will draft the termination letters, she said.

6. Include the following information in the written letter: The date that they will no longer receive care, how they can obtain copies of their medical records, and how they can find a new physician by providing contact information for a state medical association or similar organization, which often maintains a database of clinicians by specialty and location.

The letter should also state that the doctor will provide emergency care during the 30 days. Ms. Adler also recommends sending the notice by certified mail.

Dr. O’Kane said she may be more likely to give patients a second chance because she practices in a rural underserved area, and she understands that her patients don’t have many other options for health care. She also has developed a reputation for being willing to take on difficult patients that other physicians didn’t want to deal with, she said.

She encourages physicians to talk to patients to find out why, for example, they may not be compliant with medications.

“The patient may say, ‘I had to choose between paying for medications and putting food on the table,’ ” said Dr. O’Kane.

A version of this article first appeared on Medscape.com.

Low-calorie tastes sweeter with a little salt

Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.

That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.

Jason Tuinstra/Unsplash

Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.

The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.

The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.

Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch

Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.

LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.

P. aeruginosa: No problem. I think we can all guess what that little devil is up to.

Benoit-Joseph Laventie, Biozentrum, University of Basel

LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?

P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.

LOTME: Beans? What do beans have to do with it?

P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.

LOTME: Sure, we knew that. Please, continue your spilling.

P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.

LOTME: The Clash? Now we’re really confused.

P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.

LOTME: And they say you guys don’t have brains.

P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”

LOTME: Pretty clever stuff, for humans, anyway.

P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.

LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.

P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.

LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
 

What a pain in the Butt

Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.

Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.

Bildflut/Wikimedia Commons

The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.

Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.

So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.

And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.

Low-calorie tastes sweeter with a little salt

Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.

That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.

Jason Tuinstra/Unsplash

Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.

The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.

The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.

Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch

Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.

LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.

P. aeruginosa: No problem. I think we can all guess what that little devil is up to.

Benoit-Joseph Laventie, Biozentrum, University of Basel

LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?

P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.

LOTME: Beans? What do beans have to do with it?

P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.

LOTME: Sure, we knew that. Please, continue your spilling.

P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.

LOTME: The Clash? Now we’re really confused.

P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.

LOTME: And they say you guys don’t have brains.

P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”

LOTME: Pretty clever stuff, for humans, anyway.

P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.

LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.

P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.

LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
 

What a pain in the Butt

Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.

Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.

Bildflut/Wikimedia Commons

The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.

Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.

So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.

And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.

Low-calorie tastes sweeter with a little salt

Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.

That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.

Jason Tuinstra/Unsplash

Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.

The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.

The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.

Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch

Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.

LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.

P. aeruginosa: No problem. I think we can all guess what that little devil is up to.

Benoit-Joseph Laventie, Biozentrum, University of Basel

LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?

P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.

LOTME: Beans? What do beans have to do with it?

P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.

LOTME: Sure, we knew that. Please, continue your spilling.

P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.

LOTME: The Clash? Now we’re really confused.

P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.

LOTME: And they say you guys don’t have brains.

P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”

LOTME: Pretty clever stuff, for humans, anyway.

P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.

LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.

P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.

LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
 

What a pain in the Butt

Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.

Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.

Bildflut/Wikimedia Commons

The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.

Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.

So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.

And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.